Abstract
Sphingosine-1-phosphate (S1P) is an important bioactive lipid molecule in cell membrane metabolism and binds to G protein-coupled S1P receptors (S1PRs) to regulate embryonic development, physiological homeostasis, and pathogenic processes in various organs. S1PRs are lipid-sensing receptors and are therapeutic targets for drug development, including potential treatment of COVID-19. Herein, we present five cryo-electron microscopy structures of S1PRs bound to diverse drug agonists and the heterotrimeric Gi protein. Our structural and functional assays demonstrate the different binding modes of chemically distinct agonists of S1PRs, reveal the mechanical switch that activates these receptors, and provide a framework for understanding ligand selectivity and G protein coupling.
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Data availability
All data produced or analyzed in this study are included in the main text or the Supplementary Materials. The cryo-EM density maps and atomic coordinates have been deposited in the Electron Microscopy Data Bank (EMDB) and Protein Data Bank (PDB) under accession numbers EMD-31341 and 7EVY for the siponimod–S1PR1 complex; EMD-31342 and 7EVZ for cenerimod–S1PR1 complex; EMD-31343 and 7EW0 for the ozanimod–S1PR1 complex; EMD-31349 and 7EW7 for the SEW2871–S1PR1 complex; and EMD-31344 and 7EW1 for the siponimod–S1PR5 complex.
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Acknowledgements
Cryo-EM data were collected at SKLB West China Cryo-EM Center in Sichuan University and Cryo-EM Center in Southern University of Science and Technology (SUSTech), processed at SKLB Duyu High Performance Computing Center in Sichuan University. This work was supported by Sichuan University start-up funding (20822041D4057 to Z. Su), the Natural Science Foundation of China grants (82041016 and 32070049 to Z. Su); Ministry of Science and Technology of China grant (2019YFA0508800 to Z. Shao), Science and Technology department of Sichuan Province (2020YJ0208 to Z. Shao).
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Z. Shao, W.Y. and C.W. designed the cellular assays and analyzed results. Y.Y., W.W. and C.W. designed the expression constructs, purified the S1PRS–Gi–scFv16 complex, prepared the final samples for data collection toward the structures, and participated in figure and paper preparation with assistance from Q.L., Z.L., K.L. and S.Y.; Z. Su designed the cryo-EM experiments; G.J. prepared the cryo-EM grids, collected and processed cryo-EM data under the supervision of Z. Su; Y.Y., L.C. and G.J. built and refined the models under the supervision of Z. Shao and Z. Su; Z. Shao supervised the overall project, and wrote the paper.
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Yuan, Y., Jia, G., Wu, C. et al. Structures of signaling complexes of lipid receptors S1PR1 and S1PR5 reveal mechanisms of activation and drug recognition. Cell Res 31, 1263–1274 (2021). https://doi.org/10.1038/s41422-021-00566-x
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DOI: https://doi.org/10.1038/s41422-021-00566-x
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